This program is concerned with the role of behavioral factors in the development and reversal of human hypertension. Previous research in our laboratory had found that (a) intermittent behavioral stress that inhibited respiration potentiated the hypertensive effects of high sodium intake in genetically normotensive large animals, and (b) high chronic perceived stress in normotensive women was accompanied by habitual slow breathing. In addition, hypoventilatory breathing had been shown to increase circulating concentrations of an endogenous inhibitor of the sodium pump, marinobufagenin, which is increased in human hypertension. It has been well documented by others that breathing frequencies of resting humans show large individual differences that tend to remain stable over time, and that slow breathers tend to maintain higher resting levels of pCO2. By contrast, tidal volume is known to be sensitive to the energetic needs of the individual, being higher in aerobic exercise and lower in sleep, with little or no change in frequency unless volumetric capacity is exceeded. During the past year, a clinical research project testing the hypothesis that an inhibited breathing pattern is a risk factor for blood pressure sensitivity to high sodium intake in healthy women was completed. Another arm of the study tested the hypothesis that inhibited breathers had increased levels of urinary marinobufagenin excretion in response to high sodium diet. Fifty three women and seven men were recruited for the study. Thirty eight women and five men passed the qualifying physical examination and completed the 12 day study. The design involved six days on a low sodium diet (50 mmol/day) followed immediately by six days on a high sodium diet (250 mmol/day), supplemented by enteric-coasted sodium chloride capsules, prorated for body weight. Before and after low and high sodium diets, breathing pattern was monitored via the Lifeshirt (an elasticized vest that enables continuous and nonintrusive ambulatory monitoring of breathing frequency, tidal volume, and minute ventilation), blood pressure was monitored hourly over 24-hr periods via a Spacelabs oscillometric recording system, and 24-hr urinary marinobufagenin excretion via immunoassay. Compliance with the diet was determined via 24-hr urinary sodium excretion. Breathing frequency, urinary sodium excretion, body weight, and systolic blood pressure were higher, and hematocrit and hemoglobin lower (all p <.01) on the high sodium diet than on the low sodium diet. No significant differences in tidal volume, minute ventilation, or diastolic blood pressure between dietary conditions were observed. The diet-associated changes in body weight, hematocrit and hemoglobin indicate that plasma volume was expanded on the high sodium intake. Slower breathing frequencies were significantly associated with larger increases in both systolic (p <.001) and diastolic blood pressure (p <.001). No significant correlations of tidal volume or minute ventilation with either systolic or diastolic blood pressure response to sodium were observed. Multiple regression analyses showed that the associations of breathing frequency with both systolic (F1,34 = 18.5; p <.001; r2 = 0.35) and diastolic (F1,34 = 21.6; p <.001; r2 = 0.39) blood pressure response were independent of age, baseline body weight, and baseline body mass index. As expected, individual median breathing frequency and pCO2 were inversely correlated. Higher baseline systolic and diastolic blood pressures were associated with lower breathing frequency and larger changes in systolic blood pressure. Lower hemoglobin levels during high sodium intake were associated with lower breathing frequency, and with larger increases in systolic and diastolic blood pressure response to change in dietary sodium. No such associations were observed for hematocrit, indicating that the hemoglobin associations were not due to hemodilution. The results of this study strongly support the hypothesis that low breathing frequency predicts blood pressure sensitivity to change in sodium intake in normotensive women. Previous research has shown that blood pressure sensitivity of normotensive humans to high sodium intake was associated with lower plasma pH. That study suggested that a mild metabolic acidosis might characterize sodium sensitive persons, while the results of the present study indicate that a mild respiratory acidosis might be responsible. An extensive clinical literature describes hypertensive patients as deficient in emotional expressiveness, consistent with an interpretation of repression of negative affective states. The extent to which chronic respiratory inhibition is characteristic of behavioral and emotional inhibition in the natural environment remains to be explored. Sodium sensitivity of blood pressure has been shown to predict increases in resting blood pressure of young adults over succeeding years. The observation in the present study of higher pre-study blood pressure in women who were slower breathers and sodium sensitive is consistent with the conclusion that habitual slow breathing was already interacting with the American diet to elevate blood pressure above the resting blood pressure levels of faster breathers. In the natural environment, slow breathing persons might have reduced sodium appetite, in order to maintain sodium and blood pressure homeostasis. In that event, some genetic or other factors would have to intrude into the reciprocal homeostatic relationship between blood gases and sodium regulation to culminate in chronic hypertension. Additional studies are needed to clarify the pathophysiological processes by which high sodium intake of sodium sensitive persons ultimately produces the physiological adaptations that characterize chronic hypertension. Several recent studies of others have found that regular sessions of slow breathing using a portable computerized device (Resperate) is effective in reversing hypertension. We are in the process of designing a study to determine whether the mediation of this antihypertensive effect in women involves counterconditioning of inhibited breathing such as is seen in laboratory animals and humans under chronic stress. Specifically, it is hypothesized that the decreases in breathing frequency induced by the Resperate are accompanied by larger increases in tidal volume that actually increase minute ventilation and decrease pCO2. Effects of the breathing task on night-time breathing patterns in sleep will be also be investigated.